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Abstract:

A lifespan extending agent that is safe for animals, and can easily be
ingested in a form that resembles foods. A lifespan extending method is
also disclosed. In the lifespan extending agent, a rare sugar usable as a
sweetener is contained as an active ingredient.

Claims:

1. A lifespan extending agent that comprises a rare sugar usable as a
sweetener as an active ingredient.

4. The lifespan extending agent according to claim 1, wherein the rare
sugar is a sugar composition containing D-psicose and/or D-allose, the
sugar composition containing 0.5 to 17.0% D-psicose and 0.2 to 10.0%
D-allose with respect to the total sugar content.

5. The lifespan extending agent according to claim 1, wherein the rare
sugar is a sugar composition containing D-psicose and/or D-allose, the
sugar composition being a mixed sugar produced by the conversion of raw
material sugars D-glucose and/or D-fructose to include 0.5 to 17.0%
D-psicose and 0.2 to 10.0% D-allose with respect to the total sugar
content.

6. The lifespan extending agent according to claim 1, wherein the rare
sugar is a sugar composition containing D-psicose and/or D-allose, the
sugar composition being a rare sugar-containing isomerized sugar usable
as a sweetener and produced by the conversion of raw material sugars
D-glucose and/or D-fructose to include 0.5 to 17.0% D-psicose and 0.2 to
10.0% D-allose with respect to the total sugar content.

7. The lifespan extending agent according to claim 1, wherein lifespan is
extended by enhancing the production or activity of superoxide dismutase
(SOD) and catalase.

8. The lifespan extending agent according to claim 1, wherein lifespan is
extended based on the same mechanism of lifespan extension that operates
in an intake calorie restricted state.

Description:

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The present invention relates to lifespan extending agents of a
sugar composition usable as a sweetener. More specifically, the invention
relates to a lifespan extending agent of a sugar composition containing
D-psicose and/or D-allose usable as sweeteners.

[0003] 2. Description of the Related Art

[0004] Aging has become a serious social concern in Japan and other
developed countries. Among the various factors associated with the
control of lifespan and aging, caloric restriction is the most promising
for lifespan extension, and the effect of caloric restriction has been
confirmed in a wide range of biological species from nematodes to mammals
(see, for example, Youichi Nabeshima, The Biology of Aging, Medical
Science International (2000) p. 287). However, caloric restriction means
reducing the daily food intake, and is not a realistic approach.

[0005] Despite numerous studies, lifespan extension has not been fully
understood. It has been suggested that the aging phenomenon delaying
effect is not synonymous with the lifespan extending effect. For example,
it has been shown through animal experiments that vitamin E has the
effect of delaying the aging phenomena. However, studies directed to
finding the expected lifespan extending effect of vitamin E in mice and
rats have not found a clear lifespan extending effect in vitamin E
(JP-A-8-176006).

[0006] There are reports concerning lifespan extension. For example,
JP-A-2007-197374 reports that fruit (apple)-derived polyphenol prevents
heart failure or congestive heart failure, and extends the lifespan of a
model mouse with congestive heart failure. JP-A-2005-210978 reports that
oil and fat compositions of specific properties containing a-linolenic
acid and linoleic acid can extend the lifespan of rats susceptible to
stroke. These lifespan extending effects are found in model mice with
specific diseases, and in mice under high-calorie diet, and are believed
to extend lifespan by preventing or treating specific diseases or disease
conditions.

[0007] Compositions containing a specific chitosan (JP-A-2005-289839),
peroxidase (JP-A-5-124980), or activated carbon (JP-A-2010-208969) as
active ingredients are reported as compositions capable of extending the
lifespan of normal individuals. The activated carbon is not a compound
absorbable by an organism. The lifespan extending effects of the chitosan
and peroxidase are not prominent (JP-A-2010-208969).

SUMMARY OF THE INVENTION

[0008] Accordingly, there is a need for a lifespan extending agent that
can safely and effectively extend lifespan even when used continuously in
a form that resembles food. In the present invention, lifespan extension
is realized by giving rare sugars, such as D-psicose and D-allose, used
as sweeteners to animals.

[0009] It is well known that dieting by intake calorie restriction extends
the lifespan of animals such as nematodes, flies, mice, and monkeys. It
is also known that dieting by intake calorie restriction delays the onset
of age-related diseases, including, for example, diabetes mellitus,
cancer, and Alzheimer's disease, and extends the lifespan of humans. In
reality, however, dieting by intake calorie restriction is difficult to
sustain for extended time periods, and there is a need for some means to
imitate the intake calorie restriction dieting and obtain the same
effects. The present invention has been made to provide a useful
technique that solves the foregoing problem based on the same mechanism
of lifespan extension found in the related art.

[0010] The present inventors completed the present invention based on the
finding that a composition that contains a rare sugar usable as a
sweetener contributes to lifespan extension as an active ingredient.

[0011] Specifically, the gist of the present invention includes the
following lifespan extending agents (1) to (6).

[0012] (1) A lifespan extending agent that includes a rare sugar usable as
a sweetener as an active ingredient.

[0015] (4) The lifespan extending agent according to (3), wherein the rare
sugar is a sugar composition containing 0.5 to 17.0% D-psicose and 0.2 to
10.0% D-allose with respect to the sugar content.

[0016] (5) The lifespan extending agent according to (4), wherein the rare
sugar is a mixed sugar produced by the conversion of raw material sugars
D-glucose and/or D-fructose to include 0.5 to 17.0% D-psicose and 0.2 to
10.0% D-allose with respect to the total sugar content.

[0017] (6) The lifespan extending agent according to (4) or (5), wherein
the rare sugar is a rare sugar-containing isomerized sugar usable as a
sweetener.

[0018] (7) The lifespan extending agent according to any one of (1) to
(6), wherein lifespan is extended by enhancing the production or activity
of superoxide dismutase (SOD) and catalase.

[0019] (8) The lifespan extending agent according to any one of (1) to
(7), wherein lifespan is extended based on the same mechanism of lifespan
extension that operates in an intake calorie restricted state.

[0020] The present invention can provide a lifespan extending agent that
contains a rare sugar usable as a sweetener, preferably D-psicose and/or
D-allose, as an active ingredient, and that can safely and effectively
extend lifespan even when used continuously in a form that resembles
food.

[0021] More specifically, a lifespan extending agent can be provided that
has a sugar composition usable as a sweetener. The sugar composition is a
mixed sugar produced by the conversion of raw material sugars of
D-glucose and/or D-fructose to a composition including 0.5 to 17.0%
D-psicose and 0.2 to 10.0% D-allose with respect to the total sugar
content. The D-psicose and/or D-allose are contained as active
ingredients.

[0022] The lifespan extending agent can extend lifespan by enhancing the
production or activity of superoxide dismutase (SOD) and catalase.

[0023] Further, the lifespan extending agent can extend lifespan based on
the same mechanism that operates in intake calorie restriction dieting.

BRIEF DESCRIPTION OF THE DRAWINGS

[0024] FIG. 1 is a graph representing the survival rate of the nematode N2
treated with a composition containing 0.25% D-psicose.

[0025] FIG. 2 is a graph representing the survival rate of the nematode N2
treated with a composition containing 0.5% D-allose.

[0026] FIG. 3 is a graph representing the survival rate of the nematode N2
treated with a composition containing 0.5% (w/v) D-psicose.

[0027] FIG. 4 is a graph representing the survival rate of the nematode
mev-1 treated with a composition containing 0.25% (w/v) D-psicose.

[0028] FIG. 5 is a graph representing the effect of D-psicose on SOD gene
expression in nematodes N2 and mev-1.

[0029] FIG. 6 is a graph representing the effect of D-psicose on SOD
activity in nematodes N2 and mev-1.

[0030] FIG. 7 is a graph representing the effect of D-psicose on catalase
gene expression in nematodes N2 and mev-1.

[0031] FIG. 8 is a graph representing the effect of D-psicose on catalase
activity in nematode N2.

[0033] The present invention is concerned with a lifespan extending agent
in which a rare sugar usable as a sweetener is contained as an active
ingredient. The rare sugar may be, for example, D-psicose and/or
D-allose.

[0034] The lifespan extending agent of an embodiment of the present
invention extends the lifespan of animals by enhancing the production of,
for example, superoxide dismutase (SOD) and catalase. SODs are redox
enzymes that dismutate a superoxide anion (.O2-) to oxygen and hydrogen
peroxide. SODs have divalent or trivalent metal ions such as copper(II)
ions and zinc(II) ions (Cu, ZnSOD), and manganese (III) ions (MnSOD) and
iron (III) ions (FeSOD) at the active center, and are localized in large
amounts in the cytoplasm (Cu, ZnSOD) and mitochondria (MnSOD). Roles of
the SOD include reducing the oxidative stress. SODs exist in three forms,
SOD1, SOD2, and SOD3, in humans (and in all mammals and in the majority
of vertebrates). SOD1 resides in the cytoplasm, SOD2 in the mitochondria,
and SOD3 in the extracellular space. The metal ions at the active center
are copper and zinc in SOD1 and SOD3, whereas SOD2 has manganese at the
active center. Five forms of SODs exist in nematodes. SOD-1, -5 are
present in the cytoplasm, SOD-2, -3 in the mitochondria, and SOD-4 in the
extracellular space.

[0035] Catalases are redox enzymes that dismutate hydrogen peroxide to
oxygen and water, and have iron(III) ions at the active center. Catalases
are distributed in a wide range of aerobic organisms, including
microorganisms, animals and plants. In animals, catalase exists in large
amounts in a cellular organelle called peroxisome in the liver and kidney
cells, and in red blood cells. In nematodes, catalase exists in two
forms, CTL-1 and CTL-2, which reside in the cytoplasm and peroxisome,
respectively.

[0036] Considering that the SODs and catalases are commonly found in
animals, it is believed that the present invention is advantageous as a
lifespan extending agent in a wide range of animals.

[0037] Testing conducted in the present invention for lifespan measurement
using wild-type C. elegans N2 and oxygen sensitive mutant mev-1 revealed
that 0.50 (w/v) D-psicose extended the lifespan by 17% in N2 . In mev-1,
the expression level of Mn-SOD (sod-3) gene localized in mitochondria had
a 1.7-fold increase as measured by real time quantitative RT-PCR. The SOD
enzyme activity had a 1.5-fold and a 1.3-fold increase in N2 and mev-1,
respectively. Further, N2 with 0.5% (w/v) D-psicose had a 1.5-fold
increase in the gene expression levels of cytoplasm-localized catalase
and peroxisome catalases (ctl-1, ctl-2).

[0038] As demonstrated above, D-psicose exhibits the lifespan extending
effect by enhancing resistance to oxidative stress. There is a report
that the lifespan extension in nematodes in the intake calorie restricted
state is induced by antioxidant proteins (such as SODs and catalases)
regulated by the insulin/IGF signaling pathway (Braeckman, B. P. and
Vanfletren J. R., Exp Gerontol 42, 90-98 (2007)). The SOD and catalase
behaviors in response to the rare sugar share the same process as dieting
by intake calorie restriction, and the results are the same. It is
believed that the lifespan extension by the D-psicose ingestion has the
mechanism represented in FIG. 9.

[0039] The many compounds act in a similar fashion to intake calorie
restricting agents. For example, 2-deoxy-D-glucose inhibits the
glycolysis system. Resveratrol, a wine polyphenol, activates sirtuin. The
immunosuppresant rapamycin suppresses TOR. The antidiabetic agent
metformin activates AMPK. These compounds have not been put into
practical applications for reasons including high toxicity, and
insufficient effects.

[0040] On the other hand, the rare sugars used in the embodiment of the
present invention are already in use as edible sweeteners, and thus do
not have adverse effects on human body. The rare sugars, with their
desirable properties to exhibit high effects, can therefore be easily
used in practical applications.

[0041] The lifespan extending agent using the rare sugars according to an
embodiment of the present invention is described in detail.

[Rare Sugars]

[0042] Among various monosaccharide as the building blocks of sugar,
monosaccharides found only in trace amounts in nature are defined as
"rare sugars", whereas "natural monosaccharides", as represented by
D-glucose (glucose), refer to monosaccharides that are found in large
quantities in nature. A total of 59 monosaccharides are known in nature,
of which seven are classified as "natural monosaccharides", and fifty two
are as "rare sugars". The rare sugars exist only in limited quantities.
For example, D-allose is present in much smaller quantities than
D-glucose (glucose) in nature.

[0043] At present, D-psicose and D-allose are the only rare sugars mass
produced. D-psicose is a hexose (C6H12O6) present as the D
form of psicose classified as a ketohexose in the categories of rare
sugars. The D-psicose may be one obtained by different processes,
including extraction from nature, chemical syntheses, and biological
syntheses. D-allose (D-allohexose) is a hexose (C6H12O6)
with a melting point of 178° C., present as the D form of allose
classified as an aldose (aldohexose). Recently, a method of D-allose
production from D-psicose, that is a solution containing the D-psicose is
acted upon by D-xyloseisomerase to produce D-allose, is described in
JP-A-2002-17392. As described above, D-psicose and D-allose are
monosaccharides present in nature only in small amounts. And there is no
report pointing out the toxicity of these rare sugars in humans, which
suggests the toxicity against animals is low.

[0044] D-psicose has a fine, refreshing sweet taste, similar to the
sweetness of fructose, absent the discomfort associated with the
bitterness and roughness of saccharin. The degree of sweetness is about
70% of sucrose. Further, the non-caloric nature of D-psicose and D-allose
has made these rare sugars preferable as healthy sweeteners.

[0045] In one specific form, a sugar composition usable as a sweetener
containing a lifespan extending agent rare sugar as an active ingredient
is a sweetener that contains about 20 to 80 weight parts of fructose and
about 80 to 20 weight parts of glucose and psicose combined, and also
contains psicose in a proportion of 5 weight parts or more, preferably 10
weight parts or more with respect to the total 100 weight parts of
glucose and psicose in a mixture. The sweetener prevents
lifestyle-related diseases such as obesity, and has a degree of sweetness
and a taste similar to those of a table sugar (WO2008/142860).

[0046] The sweetener is a mixture of fructose, glucose, and psicose
components, and is obtained by mixing these components. Fructose and
glucose are naturally occurring common monosaccharides, and can be
isolated from nature. Fructose also can be separated from, for example, a
fructose/glucose liquid sugar obtained by the glucose isomerase treatment
of glucose. Glucose is produced from starch by hydrolysis. Psicose, a
type of rare sugar present only in limited quantities in nature, can be
obtained by treating fructose with ketohexose 3-epimerase. Aside from
being produced as a mixture of each constituent component, the sweetener
also can be produced by adding D-psicose to a fructose/glucose liquid
sugar produced from the raw material glucose acted upon by glucose
isomerase, or by converting a part of the fructose into D-psicose in the
fructose/glucose liquid sugar acted upon by D-ketose 3-epimerase.
Further, the novel sweetener containing glucose, fructose, and D-psicose
in the foregoing specific range may be produced in one step from a
glucose solution simultaneously acted upon by glucose isomerase and
D-ketose 3-epimerase. In terms of cost, it is more advantageous to use a
method in which the glucose isomerase treatment (isomerization) and the
D-ketose 3-epimerase treatment of the glucose are performed directly in
series, or a method in which the target sugar composition is obtained at
once from glucose in a mixed enzyme system of glucose isomerase and
D-ketose 3-epimerase.

[0047] D-psicose is mixed in such a proportion that the ratio of fructose
and the total of glucose and psicose ranges preferably from 80 to 20
weight parts:20 to 80 weight parts. With a fructose content of 80 parts
or more, sweetness increases but "bodies" decreases. With a fructose
content of 20 parts or less, sweetness tends to be not satisfactory. The
sweetener exhibits a degree of sweetness and a taste comparable to those
of a table sugar when psicose is contained in a proportion of 5 weight
parts or more with respect to the total 100 weight parts of glucose and
psicose. The sweetener exhibits the obesity preventing effect with a
psicose content of 10 weight parts or more.

[0048] Various producing methods are possible with the fructose/glucose
liquid sugar, glucose, or starch used as the starting raw material.

[0049] For example, (1) a fructose/glucose liquid sugar is prepared form
starch or glucose, and psicose is produced by the action of ketose
3-epimerase. (2) A decomposed glucose liquid sugar obtained by
decomposing starch is acted upon by glucose isomerase and ketose
3-epimerase in a mixed enzyme state.

[0052] A decomposed fructose/glucose liquid sugar is produced by using an
ordinary method, using, for example, a corn, potato, or ocarina starch as
the raw material with enzymes such as alphaamylase, glucoamylase, and
glucose isomerase in an immobilized or batch system. The raw material
starch and the type of the enzyme used are not limited to these. As
required, glucose solution production by acidlysis, or isomerization
using an alkali may be performed.

[0053] (2) Production of D-Psicose from Fructose/Glucose Liquid Sugar
Solution

[0054] The decomposed isomerized sugar solution produced is continuously
acted upon by epimerase to produce a mixed sugar solution of glucose,
fructose, and psicose.

[0056] Immobilized enzymes including isomerase and epimerase are charged
into an appropriate column. Then, a decomposed glucose liquid sugar is
continuously flown, and the reaction liquid is removed. Here, the
starting substance glucose may be changed to starch, and a mixed enzyme
system additionally including alphaamylase and glucoamylase may be used.

[0057] For the production of the sugar composition of the embodiment of
the present invention, a purified enzyme may be used for the glucose
isomerase that acts upon glucose for partial conversion into fructose, or
a microorganism producing the enzyme may be used. The ketohexose
3-epimerase is an enzyme that isomerizes the OH at C-3 of a ketohexose
such as fructose. Known examples of ketohexose 3-epimerase include
D-tagatose 3-epimerase, and D-psicose 3-epimerase (Japanese Patent Number
3333969: D-ketohexose.3-epimerase obtainable from Pseudomonas bacteria;
and The 3rd Symposium of International Society of Rare Sugars). The
ketohexose 3-epimerase may be a purified enzyme, an immobilized enzyme
immobilizing a microorganism producing the enzyme, or an immobilized
microorganism.

[0058] A common isomerized sugar such as HFCS containing the constituent
sugars fructose (42 weight parts) and glucose (58 weight parts) produces
glucose (58 weight parts), fructose (34 weight parts), and psicose (8
weight parts) upon being acted upon by tagatose 3-epimerase used as
ketohexose 3-epimerase. However, rather unexpectedly, glucose, when acted
upon by a mixed enzyme containing glucose isomerase and tagatose
3-epimerase, yielded a mixture of glucose (41 weight parts), fructose (48
weight parts), and psicose (11 weight parts). The both mixtures had a
degree of sweetness and a taste that more resembled the table sugar than
the fructose/glucose liquid sugar of the related art. The degree of
sweetness and the sweet taste can be adjusted by adding fructose and
glucose to these mixtures.

[0060] A rare sugar-containing isomerized sugar is an example of the sugar
composition that contains D-psicose and D-allose.

[0061] Among the sugar mixtures currently in actual use, liquid sugars, or
"isomerized sugars" or "High fructose Corn Syrup(HFCS)" as they are often
called, containing D-glucose and D-fructose have the highest use for the
production of food and beverages. Isomerized sugars include, for example,
glucose/fructose liquid sugar, fructose/glucose liquid sugar, and high
fructose liquid sugar. These sugars are collectively called isomerized
sugars, because, at present, industrial applications are only possible
through the isomerization reaction that converts D-glucose (glucose) to
D-fructose (fructose) with glucose isomerase. Any mixed sugar produced
for the purpose of obtaining a sugar composition containing a specific
hexose by taking advantage of the physiological activity of the specific
hexose represents a novel sugar composition.

[0062] For example, consider a D-psicose- and D-allose-containing
isomerized sugar produced by conversion from an "isomerized sugar"
broadly regarded as a mixed sugar whose main composition includes
D-glucose and D-fructose and targeting D-psicose and D-allose as the
hexoses having excellent physiological effects. In this case, the
resulting mixed sugar containing the target hexoses in predetermined
amounts, and having a sugar composition different from the composition of
the raw material sugar represents a novel sugar composition.

[0063] A mixed sugar of a desired composition can be produced by treating
materials under optimum conditions to satisfy the target hexose content
set in advance with respect to the sugar content according to such
factors as the type and the extent of the intended functions, usage, and
dose. Specifically, an isomerized sugar as a mixed sugar whose main
composition includes the raw material sugars D-glucose and D-fructose, or
a raw material sugar solution of D-glucose and/or D-fructose is treated
in a system that includes at least one selected from the group consisting
of a basic ion-exchange resin, an alkali, and a calcium salt. The
resulting isomerization reaction (equilibrium reaction) converts the raw
material sugars D-glucose and D-fructose into the target D-psicose and
D-allose to produce a D-psicose- and D-allose-containing sugar
composition of a sugar composition different from the composition of the
raw material isomerized sugar, and containing 0.5 to 17.0% D-psicose and
0.2 to 10.0% D-allose with respect to the sugar content (see
WO2010/113785) . For example, the hexose composition contains both
D-psicose and D-allose, preferably with 1.0 to 15.0% D-psicose and 0.4 to
8.0% D-allose, most preferably with about 2.5 to 8.0% D-psicose and 1.5
to 5.0% D-allose with respect to the total sugar content. The hexose
composition containing both D-psicose and D-allose has prominent effects,
unexpectedly exhibited by the synergy of the two not possible with the
D-psicose or D-allose alone. For example, the composition exhibits
excellent physiological effects. Specifically, such synergic effects are
seen in body weight reduction rate, body fat reduction rate, and diet
reduction rate. By the ingestion of the sugar composition containing
D-psicose and D-allose, decreases in glucose level and insulin level can
be observed. A decrease in insulin level by the sugar composition is the
effect not found in the previous testing using D-psicose or D-allose
alone.

[0064] For the sugar composition to exhibit the excellent effects above,
the proportions of D-psicose and D-allose with respect to the total sugar
content are preferably 0.5 to 15.0%, more preferably 1.0 to 15.0%, most
preferably 2.5 to 8% for D-psicose, and preferably 0.2 to 10.0%, more
preferably 0.4 to 8.0%, most preferably 1.5 to 5.0% for D-allose.

[0065] The total amount of D-psicose and D-allose ranges from preferably
0.7 to 25.0%, more preferably 1.4 to 23.0%, further most preferably 4.0
to 13.0%.

[0066] The sugar composition may be used with sweeteners such as sucrose,
sugar alcohol, aspartame, and stevia, as desired. Further, for integrity
or other desired properties, the sugar composition may be used by being
mixed in water-soluble dietary fibers of low sweetness (such as
polydextrose, inulin, and resistant dextrin), or in other physiologically
active components according to the intended use or preferences.

Use and Application of Lifespan extending agent of Embodiment of the
Present Invention

[0068] For use as food, the lifespan extending agent of the embodiment of
the present invention may be used as it is, or in the form of a diluted
solution in water or the like, an oil suspension, or an emulsion.
Further, the lifespan extending agent maybe prepared by adding a carrier
commonly used in food industry. The drinks may be non-alcohol drinks or
alcohol drinks. Examples of non-alcohol drinks include carbonated drinks,
non-carbonated drinks (such as fruit juice, and nectar) soft drink,
sports drink, tea, coffee, and hot chocolate. The alcohol drinks may be
in the form of, for example, beer, low-malt beer, third-category beer,
sake, umeshu, wine, champagne, liqueur, chuhai, or medicated liquor.

[0069] For use as a food material or food additive, the lifespan extending
agent of the embodiment of the present invention may be in the form of,
for example, a tablet, a capsule formulation, a solid agent (such as a
powder and a granule) dissolved in drinks, a semi-solid such as jelly, a
liquid (such as drinking water), and a high-concentration solution
diluted before use. Optional components, such as vitamins, carbohydrates,
dyes, and flavoring agents commonly added to food may be appropriately
mixed. The food may be given in any form, including a liquid and a solid.
The lifespan extending agent maybe given as a soft capsule formulation by
being encapsulated in gelatin or the like. The capsule uses a gelatin
coating prepared, for example, by dissolving the raw material gelatin in
water, and by adding a plasticizer (such as glycerine, and D-sorbitol) to
the gelatin solution.

[0071] The lifespan extending agent of the embodiment of the present
invention is applicable to feeds for domestic animals, domestic chickens,
and pets. For example, the lifespan extending agent may be mixed with dry
dog food, dry cat food, wet dog food, wet cat food, semi-moist dog food,
and feeds for poultry, or with feeds for domestic animals such as cows
and pigs. The feed itself may be prepared by using an ordinary method.

[0072] The lifespan extending agent of the embodiment of the present
invention can also be used for non-human animals, including, for example,
domestic mammals such as cows, horses, pigs, and sheep; birds such as
chicken, quail, and ostrich; reptiles, birds, and small mammals kept as
pets; and hatchery fish.

[0073] The medicinal agent that exploits the lifespan extending effect of
the lifespan extending agent of the embodiment of the present invention
may be used alone, or may be orally, transnasally, percutaneously, or
intravenously administered as a preparation in a suitable dosage form
such as a liquid, a granule, a subtle granule, a powder, a tablet, a
capsule formulation, a ball, an ointment, an adhesive skin patch, an
atomizing agent, a spray, and an injection after being mixed with a
suitable ordinary additive such as an excipient, a stabilizer, a
preservative, a binder, and a disintegrant.

[0074] Organic or inorganic solids, semi-solid or liquid carriers,
solubilizers, or diluents for medicinal use suited for oral
administration, nasal administration, percutaneous administration, or
intravenous administration may be used for preparing the composition of
the embodiment of the present invention as a medicinal agent. Usable as a
carrier for a medicinal agent containing the composition of the
embodiment of the present invention are water, gelatin, lactose, starch,
magnesium stearate, talc, animal•vegetable oil, benzyl alcohol,
gum, polyalkylene glycol, petroleum resin, coconut oil, lanolin, and all
other carriers that have medicinal use. Further, stabilizers, wetting
agents, emulsifiers, and salts for changing the osmotic pressure or
maintaining a suitable pH for a compounding agent also may be
appropriately used as an auxiliary medicinal agent.

[0075] The lifespan extending agent of the embodiment of the present
invention also can be used for cosmetics. Use of a soluble film for the
preparation of cosmetics and other products has become common over the
last years. For example, edible soluble films have been used as flavor
films that hold ingredients such as a flavoring agent for refreshing
purposes or for preventing a bad breath. Other applications based on
previous ideas include a mask that uses a cosmetic film holding a
moisturizer or the like, and an emulsion produced by dissolving the
lifespan extending agent in water.

[0076] It is also possible to use a soluble film proposed as having
excellent solubility and film characteristics and being preferred for use
as a wrapping material for food and drugs, or as a carrier that holds the
active ingredients of food and drugs (JP-A-2007-91696).

[0077] The lifespan extending agent of the embodiment of the present
invention thus has a wide range of applications, including food and
drinks, food additives, drugs, quasi drugs, oral compositions, cosmetics,
and feeds.

[0078] The present invention is described below in more detail based on
examples. It should be noted, however, that the present invention is in
no way limited by the following examples.

EXAMPLE 1

Experiment: Lifespan Extending Effect of D-psicose and D-allose in
Nematodes

(I) Test Method

(1) Test Animal

[0079] The wild-type N2 strain of the nematode Caenorhabditis elegans was
used.

(2) Medium

[0080] Complete S liquid medium (Sulston, J. E. and Brenner, S. (1974)
Genetics 77, 95-104) was used for the culturing of the nematode.
D-psicose or D-allose was added to the medium in 0.25% (14 mM) and 0.5%
(28 mM). The Escherichia coli (E. coli) OP50 strain was added in 30 mg
(wet weight/mL) to feed the worms. To exclude the effects of the germ
cells on lifespan, the cell division inhibitor 2'-deoxy-5-fluorouridine
(40 μM) was added.

(3) Measurements of Nematode Survival Rate and Average Lifespan

[0081] Young worms, 4 days of age, were used for the measurements of
survival rate and average lifespan. The prepared liquid medium was
dispensed onto ten plastic petri dishes having a diameter of 3.5 cm (2 mL
each). Ten nematodes were transferred to each petri dish (a total of 100
individuals), and cultured at 20° C. The samples were inoculated
into a new medium every day until day 3, and every 2 to 3 days
thereafter. Observations were made at the time of the inoculation, and
the number of survived individuals was recorded.

(II) Test Results

[0082] (1) Nematode Survival Rate over Time

[0083] FIGS. 1 and 2 represent changes in nematode survival rate over time
with addition of 0.25% and 0.5% D-allose. FIGS. 1 and 2 also show changes
in the nematode survival rate of a control group.

(2) Lifespan Extending Effect

[0084] The results of the comparison of the average lifespan calculated
from days and nematodes survival rate are as follows.

[0085] 1) The average lifespan after the treatment with 0.25% D-psicose
was 18.9 days (15.8 days for the control), which represents a 20%
increase.

[0086] 2) The average lifespan after the treatment with 0.5% D-allose was
15.8 days (12.5 days for the control), which represents a 26% increase.

(III) Results

[0087] The foregoing results confirmed a maximum of 26% increase in
average lifespan after the treatment with the composition that contained
the rare sugar as an active ingredient.

EXAMPLE 2

[0088] The wild-type N2 strain of the nematode Caenorhabditis elegans was
cultured, and lifespan was measured in the same manner as in Example 1,
except that the D-psicose was used in 0.5% (w/v). FIG. 3 shows a graph
representing the survival rate of the nematode N2 after treatment with a
D-psicose-containing composition. The average lifespan with 0.5%
D-psicose was 27 days, longer than the 23-day lifespan of the
D-psicose-free control.

EXAMPLE 3

[0089] The oxygen sensitive mutant mev-1 of the nematode Caenorhabditis
elegans was cultured, and lifespan was measured in the same manner as in
Example 1, except that the D-psicose was used in 0.25%. FIG. 4 shows a
graph representing the survival rate of the nematode mev-1 after
treatment with a D-psicose-containing composition. The average lifespan
with 0.25% D-psicose was 16 days, longer than the 12-day lifespan of the
D-psicose-free control.

EXAMPLE 4

[0090] The wild-type N2 and the oxygen sensitive mutant mev-1 of the
nematode Caenorhabditis elegans were cultured in liquid medium (10 mL)
containing 0.5% (w/v) D-psicose. The medium was dispensed onto plastic
petri dishes having a diameter of 10 cm, and approximately 1,000
nematodes were placed in each petri dish. The nematodes were cultured in
the same manner as in Example 1 except for these differences, and the
samples were collected on day 6 from the start of the culturing. FIG. 5
represents the results of the comparison of SOD mRNA gene expression
levels. For comparison, the RNA gene levels of mitochondria Mn-SOD and
cytosol Cu/Zn-SOD were measured. It can be seen that the both nematode
strains have increased expression of the SOD gene.

EXAMPLE 5

[0091] The wild-type N2 and the oxygen sensitive mutant mev-1 of the
nematode Caenorhabditis elegans were grown in the same manner as in
Example 4. The samples were collected on day 7 from the start of the
culturing, and the SOD activity in the lysate was measured. The results
are presented in FIG. 6. As is clear from the graph, the both nematode
strains with D-psicose had increased SOD activity.

EXAMPLE 6

[0092] The wild-type N2 and the oxygen sensitive mutant mev-1 of the
nematode Caenorhabditis elegans were cultured in the same manner as in
Example 4. The samples were collected on day 6 from the start of the
culturing, and the catalase mRNA gene expression levels were compared.
The results are presented in FIG. 7. For comparison, the RNA gene levels
of cytosol ctl-1 and peroxisome CTL-2 were measured. It can be seen that
the both nematode strains have increased SOD gene expression.

EXAMPLE 7

[0093] The wild-type N2 of the nematode Caenorhabditis elegans was grown
in the same manner as in Example 4. The samples were collected on day 7
from the start of the culturing, and the catalase activity in the lysate
was measured. The results are presented in FIG. 8. As is clear from the
graph, the both nematode strains with D-psicose had increased catalase
activity.

EXAMPLE 8

[0094] D-psicose was given to rats, and the growing conditions were
evaluated.

Experiment Methods

[0095] Twenty-four male Wistar rats, 3 weeks of age, were divided into
four groups (6 rats in each group), and grown for 10 months with free
access to water and the following feeds.

[0100] After growth, the body weight of each rat was measured, and an
autopsy was conducted for the weight measurement of the brain and other
organs. The measured values were given as mean values±standard
deviation, and a t-test was applied.

Results

[0101] The rat body weights (g) after growth were 452±11 for the CE-2-F
group, 436±12 for the CE-2-P group, 417±12 for the HFSC group, and
391±17 for the RSS group. A significant body weight reduction was
confirmed between the CE-2-F group and the CE-2-P group, and between the
HFSC group and the RSS group. Comparisons of organ weights between the
CE-2-F group and the CE-2-P group, and between the HFSC group and the RSS
group did not find any significant difference in the brain and muscle.

[0102] As demonstrated above by the 10-month long-term growth experiment,
the rare sugar-containing syrup containing rare sugars such as D-psicose
and D-allose either alone or in combination suppresses obesity, without
accompanied by reductions in brain weight or muscle mass often seen at
old age. The result thus suggests the possibility that the syrup
containing the rare sugars suppresses the age-related brain atrophy, and
the reduction of muscle mass related to aging.

[0103] The present invention found novel characteristics of
monosaccharides (rare sugars) found in trace amounts in nature, and
developed a novel use of the rare sugars.

[0104] The present invention can provide a lifespan extending agent that
contains rare sugars, preferably D-psicose and/or D-allose, usable as
sweeteners, and that is safe, and can be easily ingested in a form that
resembles food.

[0105] The present invention has high potential in industrial
applications, because the invention provides a novel use of rare sugars
produced by the recently developed method of producing rare sugars from
monosaccharides abundant in nature.

Patent applications by Kazuhiro Okuma, Itami-Shi JP

Patent applications by Ken Izumori, Kita-Gun JP

Patent applications by Matsutani Chemical Industry Co., Ltd.

Patent applications by NATIONAL UNIVERSITY CORPORATION KAGAWA UNIVERSITY